BLOOD PRODUCTS ADVISORY COMMITTEE

94th Meeting, April 2, 2009

Rockville, MD

 

Issue Summary

 

 

Topic III: Current Considerations on Plasma Obtained from Whole Blood Donors for Further Manufacturing Use

 

Issue:  FDA seeks the advice of the Committee on appropriate manufacturing standards for plasma products collected from Whole Blood donors to make injectable plasma derived products.

 

Introduction:

 

FDA seeks the Committee’s advice on the appropriate standards and labeling for two potential plasma products derived from whole blood donors and intended for use in further manufacturing to make injectable products.  For the purposes of this issue summary, we refer to the products as Concurrent Plasma and Component Plasma. The Committee’s discussion will be helpful as FDA explores regulatory pathways, including proposed revisions to existing regulations, to define these two plasma products as source materials to make injectables. These products potentially could replace recovered plasma for manufacture of injectable products currently regulated under short supply agreements.

 

Background:

 

Under current FDA regulations, Source Plasma (a licensed product) and recovered plasma (an unlicensed product) are used as source material to manufacture injectable plasma derived products.

 

Source Plasma (21 CFR 640.60) is an FDA licensed product collected by plasmapheresis for use in both injectable and non-injectable products.  Source Plasma standards allow collection of plasma twice within a seven day period, and incorporate measures to protect donor health due to the frequency of collection. "Infrequent” Source Plasma has been approved for manufacture and interstate distribution at some licensed blood establishments as an alternative procedure. Infrequent Source Plasma is derived from donors who meet whole blood collection standards and is collected no more than once per month.  Like Source Plasma, it must be frozen immediately. With the availability of portable devices, apheresis procedures are now commonly performed away from the primary blood collection facility and processing laboratory.  However, because of the absence of freezing capability at mobile collections, the manufacture of Source Plasma (or infrequent Source Plasma) away from the primary facility generally is infeasible.

 

Under current FDA regulations, plasma separated from whole blood collections may be labeled as recovered plasma and used in further manufacture into injectable or non-injectable products. Fresh Frozen Plasma (FFP) collected by automated blood cell separation (apheresis) may also be relabeled as recovered plasma.  However, this conversion is permitted only after its one-year expiration period when the product no longer meets the definition of FFP in the regulations.  Distribution of recovered plasma in interstate commerce without a license has historically been permitted under “short supply” regulations. [21 CFR 601.22] 

 

With recent growth in the targeted collection of cellular blood components by apheresis, whole blood collection establishments have sought changes in FDA regulations that would permit plasma collected concurrently during the apheresis procedure to be distributed immediately for further manufacturing.  Such a change would provide flexibility to blood collectors to manufacture either FFP or plasma for further manufacturing use based on current need, without concern that excess FFP might need to be held for one year or else discarded.

 

The current state of plasma storage/freezing conditions for recovered plasma varies widely and is specified in the short supply agreements between collectors and fractionators or other further manufacturers. FDA does not routinely review short supply agreements. It is known that conditions of freezing, thawing, time in contact with cells and time in the liquid state bear a relationship to preservation, activation and inactivation of labile proteins (e.g. yields of Factor VIII).  For this reason, we are considering establishing collection, freezing, and storage parameters for Concurrent Plasma and Component Plasma to ensure minimum quality suitable for the manufacture of injectable plasma derivatives.

 

Discussion: 

 

FDA is considering the definition of two new plasma products intended for use in further manufacturing of injectable or non-injectable end products.  For purposes of this discussion, we are using the following definitions. The first product, Concurrent Plasma, may be defined as a plasma product collected concurrently with a cellular product, either by whole blood collection or by apheresis. Concurrent Plasma could be labeled immediately at the time of collection, or by one time relabeling (at any time) of previously collected Fresh Frozen Plasma (or other plasma intended for use in transfusion) that has been collected concurrently with a cellular product into a product for further manufacturing. The labeling of Concurrent Plasma may include information about the separation, freezing, and storage conditions under which the product was manufactured.

 

The second new product under consideration, Component Plasma, may  be derived from one time relabeling of Fresh Frozen Plasma (or other plasma intended for use in transfusion) that has been collected by plasmapheresis as a stand-alone product. Alternatively, Component Plasma may be collected directly from a Whole Blood donor as a stand-alone plasmapheresis product intended for further manufacture. Whole Blood donors are typically recruited to donate on behalf of their local community, with the perception that their blood will be transfused to help save patient lives.  FDA is considering restrictions on the collection of Component Plasma, both to preserve the health of the donor, and to ensure the continued availability of donors of whole blood and blood components for transfusion.  Similar to the donation interval for Infrequent Source Plasma, FDA is considering that Component Plasma collection may occur no more frequently than one donation per month. The standards and labeling for Component Plasma could otherwise be similar to those proposed for Concurrent Plasma. 

 

Standards for collection, freezing, and storage

Factors involved in the definition of the new plasma products might include specified limits for collection, freezing and storage, as well as labeling that would enable the fractionators to identify the conditions under which the plasma was manufactured.

 

Since Concurrent and Component Plasma might both be collected from eligible donors meeting whole blood donor standards, the primary consideration for additional standards lies in the conditions of collection, freezing, and storage that would be reflected in product labeling.  At the Advisory Committee meeting, FDA will summarize information about processing conditions that affect the quality and safety of plasma. We will also review information obtained at the 2004 FDA sponsored workshop on plasma quality

and industry practices regarding the freezing, storage and shipping of plasma.  We will also discuss US and European regulatory requirements for plasma used for further manufacturing.

 

Briefly, conditions that affect plasma quality include: time and temperature of separation of plasma from cells; freezing; storage conditions; thawing conditions; and post thawing environment.  Certain proteins such as immunoglobulins and albumin are less affected by these conditions than other more labile proteins such as Factor VIII.  For example, Factor VIII is optimally preserved in plasma up to 6-8 hours after donation, but loses about 15% of its activity when stored 16 – 24 hours before freezing.  Similarly Factor VIII recovery is improved if freezing is rapid, to a core temperature of -25 C within 12 hr.  Adverse collection and storage conditions can promote general proteolytic activity and activate certain enzymes such as Factor XI and XII.  Enzyme activation can lead to protein fragmentation and release of small peptides, such as kinins, that can affect product quality, yield, and potentially safety.  In light of these observations, FDA is considering specifying manufacturing conditions for Concurrent and Component Plasma that that will help to assure the manufacture of safe and effective plasma products. These candidate specifications are generally consistent with current manufacturing practices.

 

 

 

 

 

 

 

 

 

Labeling

FDA currently is considering standardized categories for labeling of Concurrent Plasma and Component Plasma for key conditions of storage and freezing, so that purchasers in the US and abroad will know the salient characteristics of each product.  Other categories may be established based on further evidence showing that safe and effective products can be produced from plasma manufactured under specified conditions.  We propose the following:

 

Concurrent/  Component Plasma

Category

Examples of injectable product

Separation

Freeze

Store

Shipping

A

FVIII, vWF

IGIV, Albumin

<1 h

Freezer at < -20 C

< -20 C

< -20 C

B

FVIII, vWF

IGIV, Albumin

<24 h

Freezer at < -20 C

< -20 C

< -20 C

C

FVIII, vWF

IGIV, Albumin

<24 h

Frozen to a core temperature of < -25 C in < 12 h

< -20 C

< -20 C

D

IGIV, Albumin

<72 h

Freezer at < -20C

< -20 C

< -20 C

E

 

 

 

IGIV, Albumin

<120 h

Freezer at < -20 C

< -20 C

< -20 C

·         Shipping and storage can exceed -20 °C for < 72 h total, never > -5 °C  (never re-frozen)

 

·         The product shelf life (in the frozen state) for both products will be 10 years from date of collection.

 

·         Labeling will include an intended use statement: “Caution: For Manufacturing Use Only; Can be Used to Make Injectable or Non-injectable End Products

 

Regulatory Pathway

Creating definitions of Concurrent and Component Plasma likely would involve changes to current regulations and considerations for potential licensure of the new products.  

  

Risks and Benefits

The public health benefit of defining Concurrent and Component Plasma would be to establish standards for the collection, storage and freezing for plasma intended for further manufacturing into injectable end products.

  

The main benefit from rapid conversion of Fresh Frozen Plasma for blood establishments lies in reduction of plasma storage volumes, allowing blood establishment to gain flexibility in the management of their inventory.  However, since relabeling of Fresh Frozen Plasma under the proposed paradigm would be uni-directional, blood establishments will need to carefully monitor FFP supplies to ensure adequate availability of plasma for transfusion.  Defining Concurrent and Component Plasma in the regulations could also facilitate the collection of more male AB plasma which could facilitate current efforts to reduce the incidence of TRALI.

 

Should FDA determine that Concurrent Plasma or Component Plasma products require licensure, registered-only facilities would need to obtain a biologics license to continue interstate distribution of plasma products for further manufacture into injectable products. FDA currently considers that recovered plasma could continue to be distributed to make non-injectable products under short supply agreements.

 

 

Questions for the Committee:

 

Q1.     Does the Committee agree that the standards proposed by FDA for collection, freezing, storage and labeling for Concurrent Plasma and Component Plasma are reasonable and appropriate to ensure the quality necessary for manufacture into injectable plasma products?

 

 

Q2.      Please comment on the impact that the proposed new products would have on maintaining the voluntary donor pool that is critical to community-based voluntary blood donation.